D797N

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Aspartate → Asparagine at position 797 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Aspartate → Asparagine at position 797. ClinVar Conflicting including monogenic hearing loss + DFNA6. AlphaMissense 0.556 (borderline), ΔΔG -0.02 (neutral). Same position as D797V — second substitution at 797.

Interactive 3D Structure

Wild-type reference

Wild-type D797 — hydrogen bond to K800

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DynaMut2 mutant · D797N

Mutant N797 — hydrogen bond contact to K800 lost

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E794	E794	Preserved
Hydrogen bond	T799	T799	Preserved
Hydrogen bond	K800	K800	Preserved
Polar contact	E794	E794	Preserved
Polar contact	T799	T799	Preserved
Polar contact	K800	K800	Preserved
Van der Waals	—	T799	Gained
Hydrophobic	K800	K800	Preserved

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

-0.02kcal/mol

Destabilising — mild

AlphaMissense

0.556

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsMonogenic hearing loss; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMonogenic hearing loss + DFNA6.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2389G>A

ClinVar accessionVCV000517360

Last evaluated2025/12/05 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

Position 797 same neighbors as D797V: VAL798 (2.4 Å), ASP796 (2.4 Å), GLU794 (4.2 Å), THR799 (4.3 Å).

D797N conserves the local geometry but eliminates the charge. The D796-D797-E794 charged cluster loses one negative member. AM 0.556 borderline + dual deafness phenotype confirm severe consequence.

Amino-acid chemistry

Aspartate (D) → Asparagine (N) — carboxylate replaced by amide. Loss of charge; H-bonding preserved.

Position in the protein

C-terminal lumenal domain · position 797 (pLDDT 65 borderline). Same as D797V.

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG ≈ 0. AlphaMissense 0.556 borderline + DFNA6 confirm severe consequence.

Mechanism: charge loss from D796-D797-E794 cluster. Therapeutic: same target as D797V.

Why this matters

D797N + D797V at same position. Two charge-loss variants at the D796-D797-E794 cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D797N PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download D797N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant797–797 · in WFSL